PROJECT SUMMARY Individuals with bipolar disorder often experience functional and cognitive decline, especially in late-life. An affected ?mood network? in the brain has been proposed in bipolar disorder, which includes many of the brain regions involved in affected processes. However, mechanisms underlying changes to this network are largely unknown. Evidence from studies of animals and peripheral markers in humans suggests a role of oxidative stress, an imbalance between the production of reactive oxygen species and availability of antioxidant defenses. Our preliminary data suggest reduced availability of antioxidant defenses in the anterior cingulate cortex in bipolar disorder, particularly in older adults. This project will take a lifespan and longitudinal approach to study brain markers of oxidative stress as they relate to brain function and decline in bipolar disorder. The central hypothesis is that reduced availability of antioxidant defenses in critical regions of the ?mood network? in later-life leads to alterations in brain activation and connectivity, and ultimately to cognitive and functional decline in bipolar disorder. The long-term goal of understanding the role of oxidative stress in the pathophysiology and trajectory of bipolar disorder may lead to the identification of critical periods for intervention or the development of novel treatments. The specific aims are: 1) to examine the relationship between bipolar disorder and oxidative stress in the brain in middle- and older-aged adults, 2) to assess oxidative stress in the brain as a mechanism underlying known functional brain alterations in bipolar disorder, and 3) to conduct a pilot study to explore changes in oxidative stress and its effect on the trajectory of bipolar disorder longitudinally. Having accomplished the specific aims, this project will result in a rich dataset that will support future studies integrating oxidative stress into a larger mechanistic framework for bipolar disorder across the lifespan.